I-Bisphosphonates: Indlela yokuSebenza kunye neNtsebenzo kwiZenzo zoKliniki

by iicrosoft | Ubuhlungu obungapheliyo, impilo, Izifundo zoPhando, Unyango, Ukuphila

Bisphosphonates luhlobo lonyango / iyeza elithintela ukulahlekelwa kwethambo lokunyamekela ukunyanga izifo eziphathelene ne-osteoporosis. Zihlala ziqhotyoshelwe ukuba unyango lwe-osteoporosis. I-Bisphosphonates ineqela ezimbini ze-phosphonate. Ubungqina bubonisa ukuba banciphisa amathuba okuhlukana kwamabhinqa angemva kwe-menopausal abane-osteoporosis.

Iimfuyo zesifuba zihlaziywa ngokuqhubekayo ezigcinwa ukubonelela ukulingana, okanye i-homeostasis, ngokusebenzisa i-osteoblasts eyenza i-bone kunye ne-osteoclast echitha ithambo. I-bisphosphonates inqanda ukutyalwa kwamathambo ngokukhuthaza ama-osteoclast ukuba afakwe kwi-apoptosis okanye ukufa kweeseli.

Ngemisebenzi bisphosphonates ziquka uthintelo kunye nonyango kwamathambo, isifo Paget ngayo ithambo, Ukudlulela ithambo (kunye okanye ngaphandle hypercalcaemia), ezigula ezininzi, hyperparathyroidism zaseprayimari, enesi-, dysplasia ezinezikhondo, kunye nezinye iimeko apho kombisa ubu ithambo. Injongo yale nqaku ilandelayo kukuxubusha indlela yokwenza inxaxheba kunye nendima ekwenzeni iikliniphophononi.

Abstract

I-Bisphosphonates yi-agent ephambili kwi-arsenal ye-pharmacological yangoku ngokuchasene ne-osteoclast-mediated bone loss ngenxa ye-osteoporosis, isifo se-Paget sethambo, i-malignancies ye-metastatic kwithambo, i-myeloma eninzi, kunye ne-hypercalcemia ye-malignancy. Ukongeza ekusebenziseni ngoku okuvunyiweyo, ii-bisphosphonates zivame ukumiselwa ukukhusela kunye nokunyangwa kweentlobo zezinye iimeko zamathambo, ezifana nokuxinana kwamathambo kunye ne-osteogenesis imperfecta. Nangona kunjalo, ukuqaphela okutsha nje ukuba ukusetyenziswa kwe-bisphosphonate kuhambelana neemeko ze-pathologic ezibandakanya i-osteonecrosis yomhlathi uye walola inqanaba lokuphonononga ukusetyenziswa kwangoku ngokubanzi kwe-bisphosphonate therapy. Ukusebenzisa amagama angundoqo i-bisphosphonate kunye nokusebenza kweklinikhi kwi-PubMed yokukhangela iincwadi ukususela ngoJanuwari 1, 1998, ukuya kwi-1 kaMeyi, i-2008, sihlaziya ukuqonda kwangoku kweendlela ii-bisphosphonates ezenza ngayo imiphumo yazo kwi-osteoclasts, xubusha indima ye-bisphosphonates ekusebenzeni kwekliniki, kwaye uqaqambise ezinye iindawo ezixhalabisayo ezinxulumene nokusetyenziswa kwe-bisphosphonate.

intshayelelo

Ukususela ekungeniseni kwabo kwiinkqubo zonyango ngaphezu kwe-3 eminyaka edlulileyo, i-bisphosphonates sele isetyenziswe ngokubanzi kwiintlobo zezifo zesifo. I-Bisphosphonates isetyenziselwa ukuphathwa kwezimo ezahlukahlukeneyo ezifana neengxaki ze-squelette ezingabantwana, i-postmenopausal kunye ne-glucocorticoid-eyenziwa i-osteoporosis (GIO), kunye neethambo zesifo kwizigulana ezinezigulane. I-Bisphosphonates inokunika inzuzo enkulu yekliniki kwiimeko apho ukungalingani phakathi kwe-osteoblast-mediated bone formation kunye ne-osteoclast-mediated bone resorption ephantsi kwesifo sesifo; Nangona kunjalo, umbutho osandul 'ukwenziwa ngokutsha owenziwe nge-bisphosphonate kunye neemeko ze-pathologic, kubandakanya ukuhlawuleka kwethambo ephantsi kwezahlulo eziphethwe ngumzimba, i-osteonecrosis yomhlathi (i-ONJ), kunye nesiganeko sokwanda kwe-fibrillation ye-arrivals, uye wanyusa uhlolisiso ukusetyenziswa ngokubanzi ngokubanzi unyango lwe-bisphosphonate.

Ukupapashwa kweencwadi ukususela ngoJanuwari 1, i-1998, ukuya ku-Meyi 1, i-2008, yahlolwa ngokusetyenziswa kwe-bisphosphonate kunye neklinikhi njengemigqaliselo yophando. Amanqaku angaphezulu ayifumanekanga ekuphenyweni kweprayimari afunyaniswe nokuhlolwa kweencwadi ezichazwe kumanqaku ahlaziywe. Sinika idatha malunga nokuphuhliswa kwama-bisphosphonates njengezonyango zonyango, iinkqubo ezicetywayo apho ezi zithunywa ziqhuba iziphumo zazo, kunye neendima zamanje zonyango lwe-bisphosphonate kwindlela yokwelapha. Ukongezelela, sijongana neenkalo ezithile zokukhathalela oogqirha kwaye sibhale ingqalelo kwimiba enje ingasombulukiyo ehambelana nokusetyenziswa kwe-bisphosphonate.

Ulwakhiwo lweKhemikhali njengesiseko somsebenzi wezonyango

Ngokwesakhiwo, i-bisphosphonates ziyi-chemicals stable derivatives ye-inorganic pyrophosphate (PPi), i-compound eyenzeka ngokwemvelo apho amaqela e-2 phosphate adibaniswa yi-esterification (Umfanekiso 1, A). Ebantwini, iPPi ikhutshwa njengemveliso yezinto ezininzi ezenziwa ngumzimba; Ngaloo ndlela, inokubonwa ngokukhawuleza kwizicubu ezininzi, kubandakanywa igazi kunye nomchamo.1 Izifundo zobuvulindlela ezivela kwi-1960s zibonise ukuba i-PPi yayikwazi ukuthintela ukubala ngokuzibophelela kwi-crystals ye-hydroxyapatite, ekhokelela kwi-hypothesis yokuba ukulawulwa kwamanqanaba e-PPi ingaba yindlela yokwenza izinto. yeyiphi imineraliation yamathambo elawulwayo.2

Njengazo zendalo zendalo PPi, i-bisphosphonates inxulumene kakhulu neethambo zamaminerali kuba zibopha kwi-cryxyapatite crystals. Ngako oko, ukugcinwa kwesigxina se-bisphosphonate kuxhomekeke ekufumanekeni kweendawo ze-hydroxyapatite ezibophelelayo. I-Bisphosphonates ikhethwa ngokukhethekileyo kwiindawo zokusebenza ngokususa amathambo, njengokuba ngokuqhelekileyo kuvela kwiimeko ezibonakaliswe ngenyathelo lokukhawuleza kwegazi. I-bisphosphonate engagcinwanga kwisigxina ikhutshwe ngokukhawuleza ukusasazwa ngokugqithiswa kwemithi. Ukongeza kwikhono labo lokuvimbela ukubalwa, i-bisphosphonates inqanda ukuchithwa kwe-hydroxyapatite, ngaloo ndlela igxothise ngokugqithiseleyo i-resorption ye-bone .3 Le ntsimi ebalulekileyo ye-bisphosphonates ibangele ukuba isebenzise njengezonyango zeeklinikhi. Kutshanje, kucetyiswa ukuba i-bisphosphonates isebenze ukukhawulela zombini i-osteoblast kunye ne-osteocyte apoptosis.4,5 Ukubaluleka kokubaluleka kwesi sabelo somsebenzi we-bisphosphonate okwangoku ngokucacileyo.

Ukuguqulwa kwesakhiwo sekhemikhali ye-bisphosphonates kuye kwandise ukuhlukana phakathi koxinzelelo olusebenzayo lwe-bisphosphonate olufunekayo kumsebenzi we-antiresorptive ngokumalunga nalabo abathintela i-matrix mineralization yamathambo, okwenza ukujikeleza kwee-bisphosphonates ezisetyenziswa ngoku kwikliniki zisebenza ngokuyimfuneko kuphela ekuthinteleni i-skeletal resorption. .1 Njengoko kuboniswe kwi-Figure 1, A, isakhiwo esisisiseko se-bisphosphonates sihluke kuphela kwi-PPi kuba i-bisphosphonates iqulethe i-carbon nonhydrolyzable central; amaqela e-phosphate agudle le khabhoni esembindini ayagcinwa. Njengoko kucacisiwe kwi-Figure 1, B, kwaye ihluke kwi-PPi, phantse zonke ii-bisphosphonates ekusebenziseni iklinikhi yangoku nazo zineqela le-hydroxyl elifakwe kwikhabhoni ephakathi (ebizwa ngokuba yi-R1 isikhundla). Amaqela e-flanking phosphate abonelela ngee-bisphosphonates ngobudlelwane obuqinileyo be-hydroxyapatite crystals emathanjeni (kwaye abonwa nakwi-PPi), ngelixa i-hydroxyl motif ikwandisa ngakumbi ukukwazi kwe-bisphosphonate ukubopha i-calcium. Ngokudibeneyo, amaqela e-phosphate kunye ne-hydroxyl enza i-tertiary kunokuba i-bisphosphonate ye-bisphosphonate kunye ne-bone matrix ye-bone, inika i-bisphosphonates ngokukodwa kwabo okuphawulekayo kwithambo.1

Nangona amaqela e-phosphate kunye ne-hydroxyl ayimfuneko kwi-bisphosphonate affinity kwi-matrix yamathambo, i-moiety yokugqibela yesakhiwo (kwindawo ye-R2) ebotshelelwe kwikhabhoni esembindini yeyona nto iphambili yokumisela amandla e-bisphosphonate ekuthinteleni ukubuyiswa kwamathambo. Ubukho be-nitrogen okanye iqela le-amino kwandisa i-bisphosphonate's antiresorptive potency nge-10 ukuya kwi-10,000 ngokumalunga ne-bisphosphonates yokuqala engekho nitrogen, njenge-etidronate. equkethe i-bisphosphonates inhibit umsebenzi we-osteoclast.

Isici esibalulekileyo samachiza kwi-bisphosphonates yintsebenziswano yabo ephezulu kakhulu, kunye nokuthunyelwa ngokulandelelanayo, kwisithambo esihlobene nezinye izicubu. Ukubambisana okuphezulu kweethambo zamaminerali kuvumela i-bisphosphonates ukufezekisa ukuxinwa kweendawo eziphezulu kuyo yonke i-skeleton. Ngako oko, i-bisphosphonates ibe yipilisi yokuqala yeengxaki zamathambo ezibonakaliswe ukulungiswa ngokugqithisileyo okanye okungafanelanga ukuhlaziywa kwamathambo, apho imisebenzi ye-osteoclast kunye ne-osteoblast ayinamathele ngokukhawuleza, ekhokelela ekugqibeleni i-osteoclast-mediated bone resorption.

Iibisphosphonates zakwangoko ezingezizo initrogen (i-etidronate, i-clodronate, kunye ne-tiludronate) (Umfanekiso 1, B) zithathwa njengee-bisphosphonates zesizukulwana sokuqala. Ngenxa yokufana kwabo kwesakhiwo kunye ne-PPi, i-bisphosphonates engekho i-nitrogen-engenayo i-nitrogen idityaniswe kwiimolekyuli ze-adenosine triphosphate (ATP) esanda kwakhiwa yiklasi II aminoacyl �transfer RNA synthetases emva kwe-osteoclast-mediated uptake from the bone mineral surface.1 Intracellular accumu kwezi analogu ze-ATP ezingenahydrolyzable kukholelwa ukuba ziyi-cytotoxic kwi-osteoclasts kuba zithintela iinkqubo ezininzi zeselula ezixhomekeke kwi-ATP, ekhokelela kwi-osteoclast apoptosis.

Ngokungafani ne-bisphosphonates yokuqala, i-bisphosphonates yesizukulwana sesibini kunye nesesithathu (i-alendronate, i-risedronate, i-ibandronate, i-pamidronate, kunye ne-zoledronic acid) ine-nitrogen equkethe i-R2 ye-side chain (Umfanekiso 1, C). Indlela apho i-nitrogen-equlethe i-bisphosphonates ikhuthaza i-osteoclast apoptosis yahlukile kuleyo ye-bisphosphonates engena-nitrogen. Njengoko kuboniswe kakuhle kwizifundo zamva nje, i-nitrogen-equkethe i-bisphosphonates ibophelela kwaye inqande umsebenzi we-farnesyl pyrophosphate synthase, i-enzyme ephambili yokulawula kwindlela ye-mevalonic acid ebalulekileyo ekuveliseni i-cholesterol, ezinye i-sterols, kunye ne-isoprenoid lipids6,7 (Umfanekiso 2, A). i-analog inokwenzeka ukuba ngumsebenzi othe ngqo wokukwazi ukwenza i-bisphosphonates ngokukhetha ukunamathela kunye nokugcinwa ngaphakathi kwethambo ngaphambi kwe-endocytosis ngaphakathi kwe-osteoclasts ngexesha lokuchithwa kwe-osteoclast-mediated bone mineral digestion kunye ne-matrix digestion (Umfanekiso 2, B). Ngenxa yokuba phantse zonke izigulana ngoku zifumana unyango nge-bisphosphonates enamandla kakhulu ye-nitrogen kune-bisphosphonates yangaphambili engekho-nitrogen, intsalela yolu hlaziyo igxile kolu didi lwamva nje lwe-bisphosphonates.

Iimpawu zeeKliniki ezongezelelweyo

Nangona i-bisphosphonate-mediated induction ye-osteoclast apoptosis ayinakulinganiswa ngokuthe ngqo ngaphakathi kwendawo yeklinikhi, ukunciphisa okwethutyana kwiimpawu ze-biochemical ze-bone resorption (oku kukuthi i-amino- kunye ne-carboxyl-terminal breakdown products of type 1 collagen in serum kunye nomchamo) emva kokuqaliswa kwe-bisphosphonate kuqwalaselwa i-surrogate ethembekileyo ethembekileyo yokusebenza kwe-bisphosphonate kunye namandla. Ukunyanzeliswa okuphezulu kwe-bone resorption kwenzeka ngaphakathi malunga neenyanga ze-3 zokuqaliswa konyango lwe-bisphosphonate yomlomo olunikezwa imihla ngemihla, ngeveki, okanye ngenyanga kwaye luhlala luhlala luhlala luhlala luhlala luhlala luqhubekayo kunye nokuqhubeka nonyango. unyango lwe-bisphosphonate.

Njengoko kunokulindeleke, ubude bexinzelelo buninzi luyinto yokusebenza kwe-bisphosphonate ye-mineral matrix ebophayo, njengokuba i-bisphosphonate enamandla kakhulu, i-zoledronic acid, kwi-dose ye-4 mg13 okanye i-5 mg (i dose evunywe yi-Food and Drug Administration [FDA] ye-osteoporosis), i-14 iyanciphisa ngokuphumelelayo iimpawu zezinto eziphilayo ze-bone resorption ukuya kwi-1 ngonyaka kwabasetyhini abane-postmenopausal osteoporosis. Nangona i-half-biologicalic half-life-life of the now-nitrogen-containing containing bisphosphonates ihlala ingumxholo weengxoxo ngokubanzi ngenxa yeengxaki zobunzima ezifunekayo ukucacisa amanqanaba e-bisphosphonate kumchamo kunye ne-serum, ukuqikelela ukuba i-alfronate ye-bisphosphonate enamandla ibonisa ubuncinane bemizuzu engaphezu kwe-biologic Iminyaka eyi-10 emva kokulawulwa kwe-single dose IV.15

Into ebalulekileyo elawula i-pharmacology yeklinikhi ye-bisphosphonates kukufumaneka kwabo. Njengeklasi, i-bisphosphonates i-hydrophilic kakhulu. Ngokunjalo, azifakwanga kakuhle kumathambo esiswini emva kolawulo lomlomo (ngokubanzi ngokufakwa kwe- <1% yedosi yomlomo), endaweni yoko bethutha iiparacellular zothutho kuba bengengabo abomlomo. igcinwe emathanjeni, kanti intsalela iyasuswa kumchamo ngaphandle kokudityaniswa. Ukufunyanwa kwamathambo kunye nokugcinwa ikakhulu kuxhomekeke kumbandela wokubamba (umsebenzi we-renal, inqanaba elixhaphakileyo lokufunyanwa kwethambo, kunye nokufumaneka kwesiza) kunye ne-bisphosphonate potency ye-matrix.16 Inani le-bisphosphonate eligciniweyo emva kolawulo lomlomo okanye lwe-IV lahluka kakhulu phakathi kwezigulana kunye Kuzo zonke iimeko zeklinikhi kwaye kukholelwa ikakhulu ukuba zibonakalisa umahluko kwinguqulelo yethambo.50

Isithintelo sangaphambili kwizigulane ezininzi ezichazwe ngomlomo we-bisphosphonate yonyango kwakuyiziphazamiso ezinxulumene nokulawulwa komlomo kwansuku zonke (ezifuna izigulane ukuba zihlale zilungele imizuzu ye-30 kwaye ziyeke ukutya nantoni na ii-2 iiyure ngaphambi kwaye ubuncinci imizuzu eyi-30 emva kokungena kwipilisi) kwaye iyafana ukunxulumana neempawu zesisu. Uphuhliso olutshanje lwama-pharmacologically alinganayo okuvumela ukuba kube kanye ngeveki (i-alendronate okanye i-risedronate) okanye kwinyanga nganye (ibandronate okanye i-risedronate) ukulawulwa komlomo kuye kwathintela kakhulu ukuhanjiswa kwe-bisphosphonate kwizigulane ezininzi ezinokuthi zilungele (kunye nokunamathela kwonyango) yinkinga kwaye ngokufanayo kuholele kwizinga eliphezulu lokunamathela.17,18 Ngaphezu koko, ukufumaneka kwe-IV ukulungiselela (i-pamidronate, ibandronate, kunye ne-zoledronic acid), leyo yezona nkalo zonyango zifuna ukuba zingaphantsi kangako, ziye zaphelisa iziphumo ezimbi ezibangelwa zizigulane ezilawulwe i-bisphosphonates zomlomo, nangona isantya sempembelelo yesigaba esicacileyo esibonakaliswa yimpawu ezinjengomkhuhlane (i-low-grade fiver, i-myalgias kunye ne-arthralgias, okanye intloko) yanda kwizigulane ezitholayo i-IV kunokuba unyango lwe-bisphosphonate ngomlomo.14

Indima kwiZenzo zoKliniki

Njengoko sele kukhankanyiwe ngasentla, i-bisphosphonates ikhuthaza i-apoptosis ye-osteoclasts ebandakanyekayo ekuthotyweni kweeminerali kwindawo yamathambo. Ngako oko, i-bisphosphonates ibe yonyango oluphambili lokulawula iimeko zamathambo ezibonakaliswe ngokunyuka kwe-osteoclast-mediated bone resorption. I-resorption enjalo iphantsi kweemeko ezininzi ze-pathologic apho i-bisphosphonates isetyenziswa ngoku ngokuqhelekileyo, kubandakanywa neendlela ezininzi ze-osteoporosis (ulutsha, i-postmenopausal okanye i-involutional [senile], i-glucocorticoid-induced, i-transplant-induced, immobility-induced, kunye ne-androgen-deprivation), Isifo sePaget yethambo, i-osteogenesis imperfecta (OI), i-hypercalcemia, kunye ne-malignancy metastatic kwithambo.

Nangona i-bisphosphonates nganye ye-nitrogen inamandla ngakumbi kune-bisphosphonates engekho i-nitrogen, ukukwazi kwabo ukucinezela umsebenzi we-osteoclast (njengoko kulinganiswa ngamanqaku e-biochemical of the bone turnover) ayahluka. Nangona kunjalo, ukuba ukunyanzeliswa okuphezulu kokuguqulwa kwamathambo kubalulekile ekuthinteleni ukuphuka kuya kuhlala kugqitywa. Enyanisweni, idatha ibonisa ukuba ukuthotyelwa kwexesha elide lonyango lwe-bisphosphonate, kunokuba i-bisphosphonate ethile isetyenzisiweyo, iyona nto ibaluleke kakhulu ekunqumeni ukuphumelela kwonyango lokunciphisa ingozi yokuphuka. ukujongana neenkxalabo zesigulane malunga nokhuseleko lwamayeza kunye nexesha, oogqirha banokuphucula kakhulu ukubambelela.

iOsteoporosis

Iimeko eziqhelekileyo zeklinikhi apho i-bhophosphonate yonyango isetyenziselwa i-osteoporosis, imeko ye-skeletal ebonakaliswe yimandla amathambo okonakele okwenyuka kwingozi yokuphuka. Njengokuba kuphawuliwe ngaphambili, i-osteoporosis iyisifo esiyinyango esisodwa esinesifo esithile, kuquka ukulahlekelwa kwe-hormone (i-postmenopausal kunye ne-androgen-inkunkuma), iatrogenic (i-glucocorticoid-induced and transplant-related-related), ngokomzimba (ukungahambi kakuhle) kunye nemfuza (isib. Idibeneyo). Ngokuqhelekileyo ezi meko ziyafumaneka kwizigulane ngamnye.

I-postmenopausal osteoporosis ibonakala ngokungalingani phakathi kwe-osteoclast-mediated bone resorption kunye ne-osteoblast-mediated bone formation eyenziwe ukuba i-bone resorption yanda. Ukungalingani ngokulinganayo kukukhokelela ekunciphiseni kwamathambo, ukuphazamiseka kwethambo le-microarchitecture, kunye nokwanda komngcipheko wokuqhekeka. Ngexesha elidlulileyo leminyaka ye-2, unyango lwe-bisphosphonate lube yingenelelo yokungena kweklinikhi kwi-postmenopausal osteoporosis ngenxa yokukwazi ukwenza i-bisphosphonates ukuba ikhusele ngokunyanisekileyo umsebenzi we-osteoclast kwaye ngaloo ndlela uyalinciphisa i-bone resorption. Ukunciphisa ukuphulwa komzimba kunye nokunyuka kwama-bone kwi-bone brains kubonakala ukuba kubangelwa ukuhla kwexesha lokuqalisa ukusebenza kweeyunithi zokuvuselela ezintsha ezenziwe ngama-osteoclasts, kunye nokulondolozwa ngokulinganayo (ubuncinane ekuqaleni) kwemisebenzi ye-osteoblast. Ngaloo ndlela, ukuqiniswa kokuqala kunye nokugcinwa kokuxhamla kwintsebenziswano kuvumela ixesha lokubambiswa kwemineral mineral kwi-scaffold yolwakhiwo ukuba lide, ngokwandisa ipesenteji yamathambo ezakhiwo ezifikelela kwizinga eliphezulu lokunciphisa umgangatho we-mineralization.22 Ukwanda kwinqanaba elide I-mineralized i-skeletal mineralization iphantsi kokuphuculwe kwintsebenziswano yethambo kunye nokunciphisa ingozi yokuphulwa komzimba emva kwonyango ye-bisphosphonate.

Okubalulekileyo, le ndima ye-bisphosphonates igxininiswe ngokungangqalanga kukupheliswa kwangoko kwengalo ye-estrogen kunye neprogesterone ye-Women's Health Initiative (WHI), ngenxa yenkxalabo malunga nokunyuka kwamazinga esifo se-coronary artery kunye nomhlaza wamabele phakathi kwabasetyhini abafumana unyango lwehomoni. Kwabaninzi oogqirha kunye nezigulane, iziphumo ze-WHI zinciphisa ngokufanelekileyo umkhuba wokunyanga i-postmenopausal osteoporosis kunye ne-hormone yonyango yokutshintshwa, nangona ubungqina obuqinileyo obunikwe kwi-WHI kunye nezifundo zangaphambili ukuba i-estrogen iphumelele kakhulu ekukhuseleni ukuphuka.23

Phakathi kwe-bisphosphonates yomlomo, zombini i-alendronate kunye ne-risedronate ziye zaboniswa ngokucacileyo ukunciphisa inani le-vertebral24�26 kunye ne-hip fractures, i-24,27 inkqubela phambili ye-vertebral deformity, kunye nokulahleka kobude kubafazi be-postmenopausal abane-osteoporosis. kumalungiselelo omlomo kunye ne-IV, kubonakaliswe ukunciphisa kuphela umngcipheko we-vertebral fracture, i-28 nangona uqikelelo lwesayizi yesampula esetyenzisiweyo aluzange luvumele amandla aneleyo ukuba abone umphumo kwi-nonvertebral okanye i-hip fractures. Ukunciphisa ingozi yokuphulwa kwengozi kwiindawo ze-vertebral, i-hip, kunye ne-nonvertebral kubasetyhini be-post-menopausal abane-osteoporosis eyaziwayo emva kweminyaka eyi-29,30 yonyango lwe-bisphosphonate ifaniswa kwiThebhile.

Ukunciphisa iziganeko zokuphuka kwenzeka ngaphambi kokuba utshintsho olubonakalisiweyo ( lulinganiswe nge-double-energy x-ray absorptiometry [DXA]) kwi-bone mineral density (BMD), ebonisa ukuba ukuzinziswa kwe-microarchitecture ekhoyo yamathambo okanye ukunciphisa ukuguqulwa kwamathambo kwanele ukunciphisa ingozi yokuphuka.31 Imihla ngemihla. Ukusetyenziswa kwe-alendronate kwimilinganiselo ye-10 mg ukuya kuthi ga kwi-10 iminyaka yayinyamezeleke kwaye yayingahambelani neziphumo ezibi zamathambo.32 Nangona phantse zonke iimvavanyo ze-osteoporosis apho unyango lwe-bisphosphonate lusetyenzisiwe lubandakanya abafazi be-postmenopausal, izilingo eziqhelekileyo eziye zavavanya amadoda ane-diagnostic. okanye ubunzima bethambo eliphantsi okanye i-osteoporosis ibonise iimpendulo ezifanayo kwi-bisphosphonate therapy.33�35

Kwi-Fracture Intervention Trial Ixesha elide lokuLandiswa, abafazi be-postmenopausal abaneentloko ezisezantsi zeentombi ze-BMD (kodwa kungekhona ngokubhekiselele kwi-DXA-defined osteoporosis) baphathwe nge-alendronate yemihla ngemihla ye-5 iminyaka baze bafumane i-alendronate okanye indawo ye-placebo kwiminyaka eyi-5 eyongezelelweyo. Abasetyhini abayeke ukwelashwa kwe-alendronate babenemilinganiselo ebalulekileyo, nangona iikliniki ezincinci, iyancipha kwi-BMD kunye nokunyuka okuhambelana nabakhweli bezinto eziphilayo. Nangona kunjalo, kwakukho ingozi ephakamileyo (kunye neyobalo-nyiweyo) yeengcambu ze-vertebral fractures kwiqela le-placebo (ingozi epheleleyo, i-36%), kodwa oku kwakungeyona ndawo yokugqibela yokufunda okanye yesibini. Ucwaningo olusesikweni lokupheliswa kwe-alendronate kunye namandla amaninzi okuvavanya ukuvavanywa emva kokuyeka ukuphela kweyona ndawo yokugqibela okanye enye ye-bisphosphonates ayengakagqiba ukuba, ubuncinane ezinye izigulane ezine-postmenopausal osteoporosis, ikhefu leziyobisi linokuqiqa emva kwexesha le-bhosphosphonate .

Izifundo zokuqala zisebenzisa i-dosphosphonate dosing yansuku zonke; Uphando olutshanje lujolise kwiveki nganye (i-alendronate kunye ne-risedronate) okanye ngenyanga (ibandronate, kunye ne-recently-risedronate37), ii-regimens ezikholelwa ukuba zifana ne-pharmacodynamic equivalence kwi-dosing ye-day. Nangona kunjalo, zonke izifundo ukuya kutsho ngokusebenzisa i-weekly weekly okanye ngenyanga yonyango ye-bisphosphonate zithembele kwiimpawu zokuxhaswa kwamatyala, njengabakishi bezinto ezinokwakheka kwemfuyo ye-bone resorption okanye utshintsho kwi-BMD elinganiselwe yi-DXA, kunokuba iziphumo zokuphulwa kweprayimari, ukuzimisela ukusebenza. Ngokwahlukileyo, isilingo seBONE, apho i-bandronate yomlomo eyayilawulwa ngayo yonke imihla ngemihla ye-12 yonke inyanga ye-3, yanciphisa i-vertebral fractures nge-dosing encane, i-30 nangona le regimen ye-dosing ayigunyazisiwe yi-FDA yokunyangwa kwe-postmenopausal osteoporosis. Nangona kunjalo, unyango lweveki okanye lwanyanga zonke lukholelwa ukuba lufana nolwabiwo lwe-contraction of fractions and has become the standard of care.

Ngoku kutshanje, zombini i-ibandronate kunye ne-zoledronic acid ivunyiwe ukuba i-IV isebenze ukuphatha i-postmenopausal osteoporosis. Nangona ibandronate ivunyelwe ukulawulwa kwekota, i-zoledronic acid ivunyiwe ukuba ilawulwe kanye ngonyaka. Ngethuba leZiphumo zeMpilo ze-3 zonyaka kunye neNgcembelelo eNcitshiswayo nge-Zoledronic Acid, emva kwexesha lokufunda (HORIZON) ngonyaka, ulawulo lwe-IV lwe-zoledronic acid lukhokelela ekunciphiseni okukhulu kwi-vertebral (i-70% yokunciphisa%), i-hip (i-41% ukunciphisa), kunye ne-nonverbral (25). ukunciphisa i-%), ukunyuka okubalulekileyo kwi-BMD kwi-lumbar umlenze, umlenze kunye nentamo ye-femal.14 Ukongezelela, ukulawulwa kwe-IV zoledronic acid kwimihla ye-90 yokuqhaqha isaphulelo sokuqhaqhaqhaqho kunye nonyaka emva koko kuboniswe ukunciphisa isiganeko I-35% kwaye inxulumene nokunciphisa i-28% ekufeni.38 Ngaphezu koko, kwizigulane ezaphathwa nge-alendronate yeveki ubuncinane ubuncinane be-1 kunyaka, ukutshintshela kwi-yoledronic acid yonyaka kwakungekho ngaphantsi kokuqhubeka kwe-alendronate, kodwa ngonyaka wayekhethwa yizigulane.39 Ingaba izilungiso ze-IV ziza kukhethwa kwi-formphosphonate formulations zokulawulwa kwe-postmenopausal osteoporosis okanye af Ukuqhekeka kwe-hip fracture akungaziwa. Nangona kunjalo, kucacile ukuba ukuhanjiswa kwe-bhosphosphonate kubaluleke ngakumbi ukuba ukunyamezela okanye ukunyamezela isisu kuyinqobo kumathambo omlomo okanye ukuba izigulane zikhetha ukulungelelaniswa kwe-IV bhosphosphonate.

Ekugqibeleni, izifundo ezininzi zijolise kwixesha elifanelekileyo lonyango lwe-bisphosphonate yokulawula i-osteoporosis ngokubambisana namanye ama-pharmacological agents anomsebenzi wamathambo. Nangona ukudibanisa i-bisphosphonate kunye ne-estrogen okanye i-estrogen-receptor modulator ekhethiweyo i-raloxifene ikhokelela ekunyuseni kancinci kancinci kwi-BMD kunonyango nge-bisphosphonate yodwa, akukho datha yovavanyo lweklinikhi elungileyo kwiinqanaba zokuphuka kwenkxaso yokusetyenziswa kwesiqhelo kwezi zidibaniselwano.40,41 Ezinye izifundo. baye bavavanya izigulane ezifumana i-1�84 i-hormone ye-parathyroid yabantu (PTH) okanye i-PTH fragment 1�34 (teriparatide) . wenza unyango oluhambelanayo usebenzisa i-bisphosphonate kunye nokuba yi-PTH okanye i-teriparatide.42 Iziphumo ze-anabolic ze-skeletal ezinamandla kakhulu zibonwa kwizigulane ezifumana unyango lokuqala lwe-PTH kwaye emva koko zigcinwe nge-bisphosphonate therapy.44

I-Glucocorticoid-Yenza i-Osteoporosis kunye ne-Transplant-Associated Osteoporosis

Nangona i-bisphosphonates ibe yintloko yokukhetha unyango lwe-postmenopausal osteoporosis, bambalwa abaqaphela ukuba unyango lwe-glucocorticoid lubangela ukulahlekelwa kwethambo. Uphando olutshanje lufumene ukuba ezininzi izigulane ezithobela i-long-term ye-glucocorticoid unyango azifumaneki uvavanyo lwe-BMD okanye imithi yonyango kwanoma yiyiphi na imithi yokulawulwa kwe-osteoporosis. I-49 Izilingo zamachiza ezininzi ngoku sele zizimisele ukuba i-bisphosphonates iphumelele kakhulu ekunciphiseni ukulahlekelwa kwethambo kwizigulane ezitholayo i-glucocorticoids okanye i-transplants . Umsebenzi wamva uye wabonisa ukuba, kwizigulane ezithatha umthamo wemihla ngemihla ye-7.5 mg ye-prednisone, i-alendronate inqande ukulahleka kwethambo ngokuphumelelayo kunokuba i-vitamin D3 analogue alfacalcidol.50 Ngaphezulu, kwizigulane eziphathwe nge-glucocorticoid zengozini enkulu yokuphulwa, kuquka ezo kunye nembali yezahluko, abo abane-arthritis ye-rheumatoid, okanye abo bafumana iqondo eliphezulu le-glucocorticoid, unyango lwe-bisphosphonate lugqibe kakhulu.51

Ngokufanelekileyo, i-risedronate ivunyiwe e-United States yokukhusela kunye nonyango lwe-GIO kunye ne-alendronate yonyango lwe-GIO. Zombini zisebenza ngakumbi xa i-calcium intake kunye ne-vitamin D intake yanele. Kwakhona, unyango lwe-IV kunye ne-pamidronate okanye i-ibandronate lubonakaliswe ukunciphisa ukulahleka kwamathambo kwi-glucocorticoid therapy, i-52,53 nangona ingakavunyelwanga kwesi sibonakaliso. Ngokucacileyo, uphando oluninzi luye lwabhala ukuba zombini i-oral kunye ne-IV ye-bisphosphonate yonyango iyakwazi ukunciphisa ilahleko yethambo eyenzeka rhoqo kunye ne-organ organ54�58 okanye i-bone marrow transplant.59�62

Ekugqibeleni, uphando olutshanje lubonise ukuba izigulane ezine-GIO eziphathwe nge-teriparatide zanda kakhulu ukwanda kwe-BMD kunye neentsholongwane ezincinci ze-vertebral fractures kunezigulane ezafumana i-alendronate kwimihla ye-18 inyanga.63 Ingaba i-teriparatide ifanele ithathe unyango lwe-bisphosphonate njengonyango olukhethiweyo kwizigulane ezinokwakheka kwe-osteoporosis ezithobela i-long-term ye-glucocorticoid unyango.

Ukungahambi kakuhle-Ukunyuka kwe-Osteoporosis kunye Nezinye izizathu zokulahleka kweThambo eLawulayo

Izigulane ezingenakunyuswa, ezifana nezo zitshatyalaliswa kwintshontsho yesigxina okanye umcimbi we-cerebrovascular, ilahlekelwa yithenda ngokukhawuleza, ekhokelela kwingozi enkulu yokwaphuka, i-hypercalcemia, kunye nephrolithiasis rhoqo. Zomlomo zomlomo (i-alendronate) 64 kunye ne-IV (pamidronate) I-65 yonyango ye-bisphosphonate iboniswe ukuba ilukhumbule ukulahlekelwa kwethambo kunye nokunciphisa amanqaku e-biochemical of resorption yamathambo. Nangona kunjalo, inani leemvavanyo zeklinikhi ezenziwa ngokusetyenziswa kwezi zibini zihlala zincinci. Ngaloo ndlela, i-incracture incidence, rates of nephrolithiasis, kunye nokukhuseleka kwexesha elide kuya kuhlala kunqunywe.

Ngokungafani nokulahlekelwa kwethambo okwenziwe ngokubanzi emva kwe-immobilization, ukulahleka kwethambo ephucukileyo kwendawo ye-periprosthetic kunye nokufakelwa kwezinto ezinxulumene nokuxhamla kwimeko edlalwa rhoqo kwizigulane ezithatha i-hip arthroplasty. Bobabini i-alendronate66 kunye ne-risedronate67 bayayilumkisa le ntlupheko ye-periprosthetic bone loss of the femur, kodwa nangona i-long-effect ye-bhonphosphonate unyango ngokugcinwa kwengqibelelo ingakabikwa.

I-Paget Izifo zeThambo

Nangona i-postmenopausal osteoporosis ibonakala ngokulahleka kwethambo ngokubanzi ukusuka kumsebenzi wokwandisa i-osteoclast, isifo se-Paget sethambo sibandakanya i-1 okanye iindawo ezininzi zokulungiswa kwamathambo, apho ukukhawuleza kwe-osteoclast-mediated bone resorption ilandelwa yi-osteoblast-mediated bone deposition.68 Umxube obangelwayo. Ithambo elilukiweyo elingekho kakuhle kunye ne-lamellar lihlala likhokelela kwiintlungu, ukwaphuka, kunye nokukhubazeka okunzulu, kubandakanya ukugoba kwamathambo amade anobunzima, ukukhulisa ukhakhayi, okanye ezinye iziphene ezininzi zamathambo. Njengelitye lembombo kunyango lwePaget isifo sethambo, ii-bisphosphonates zicinezela kakhulu ukonyuka kwamathambo okuphantsi kwesi sifo, okukhokelela ekubeni kuqheleke amanqanaba e-alkaline phosphatase esetyenziselwa ukujonga umsebenzi wesifo. I-Oral (i-alendronate69 kunye ne-risedronate70) kunye ne-IV (i-pamidronate71 kunye ne-zoledronic acid72) i-bisphosphonates zonke zivunyiwe yi-FDA kunyango lwe-Paget yesifo samathambo kwaye zithathe indawo yonyango lwangaphambili oluvunyiweyo lwe-FDA (engekho i-nitrogen-equkethe i-bisphosphosphosphonin kunye ne-nitrogen) kuba ukukwazi kwabo ukucinezela umsebenzi we-osteoclast kuphezulu.

Bisphosphonates e Malignancy

Uninzi lweengqungquthela zi-osteotropic kwaye ziza kufakwa kwi-skeleton (kubandakanywa kodwa zingagqibekanga kwizonyanya eziphambili zesifuba, i-prostate, imiphunga, okanye iinjongo) okanye zikhule ngokuyinhloko ngaphakathi komnatha wethambo (ezininzi ze-myeloma), apho oku kukhula kuqhubela phambili kwi-hypercalcemia, iintlungu zethambo, ukutshabalaliswa kwamathambo, kunye neentlobo ze-pathologic fractures. Enyanisweni, i-skeleton yindawo eqhelekileyo yezifo ze-metastatic, kunye ne-90% okanye ngaphezulu kwezigulane ezinomdlavuza ophezulu zihlakulela izilonda ze-skeletal.73

Umhlaza webele

Kwizigulane ezinomhlaza webele we-metastatic ukuya kwithambo, unyango ngamalungiselelo e-IV e-pamidronate, i-74�76 zoledronic acid, i-77,78 kunye ne-ibandronate79 ibonakaliswe ukukhulula kakhulu intlungu ye-skeletal kunye nokunciphisa iingxaki ze-skeletal. Kwi-nitrogen yomlomo equkethe i-bisphosphonates, i-ibandronate kuphela (enikwe kwi-dosage yemihla ngemihla ye-50 mg) isebenze ekunciphiseni intlungu yethambo kunye nokunciphisa iingxaki ze-skeletal zomhlaza webele.80,81

Ukusetyenziswa kwe-bisphosphonate kunendima echaseneyo kwonyango lwabasetyhini abanomdlavuza wesibeleko kodwa akukho bungqina bokuba i-metastases ye-skeletal engaziwayo kodwa ingacetyiswa ngolu hlobo lokufumanisa ukuba abesifazana abanomdlavuza ongasesekiyo lwezonyango othotyelwe kliniki abafumene i-clodronate kwiminyaka ye-2 banemihla ukuphuhliswa kweethambo zesistim ngelixa befumana unyango lwe-bisphosphonate, kunye nokunciphisa ukufa kwabantu bonke xa belandelwa iminyaka eyi-6.82 Nangona unyango lwe-bisphosphonate kubafazi abafumana unyango lwe-hormone yomhlaza wesifuba uye wanyuswa ingqalelo, indima ebalulekileyo yokunciphisa ukubuyiswa kwethambo ukugcina ingqibelelo yamathambo (ngokukodwa phakathi kwabafazi be-premenopausal apho i-esrogen iyakwazi ukunyanzeliswa kwe-pharmacological). I-83 Iindlela ezifanelekileyo zokulawula i-bisphosphonate ezihambelana neendlela ezininzi zokufumaneka kweemveliso ze-ovarian ovarian zihlala zichongwe, nangona ama-zol I-acid ye-edronic (i-4 mg IV inikezelwa zonke iinyanga ze-6) I-84 ibonakaliswe kutshanje ukuthintela ukulahleka kwethambo kubasetyhini be-premenopausal bafumana unyango lwe-endocrine olusisiseko somhlaza wesibeleko se-hormone. Ngokufanayo, kubasetyhini abasemva kwe-hormone exhomekeke kwi-hormone, i-risedronate yomlomo yanyanga zonke iboniswe ukuthintela ukulahleka kwethambo kulabo bafumana unyango lwe-aromatase inhibitor.85

Cancer Cancer

Umhlaza wamabele ubonakaliswa ngamanxeba e-osteolytic, kodwa i-skeletal metastases evela kumhlaza we-prostate ichazwe njenge-osteoblastic. Indima yokunyuka kwethambo kwi-metastatic cancer ye-prostate iye yabonwa kutshanje.86 Phakathi kwe-bisphosphonates, i-zoledronic acid kuphela ibonakaliswe ukunciphisa iziganeko ezinxulumene nethambo lamathambo kumadoda anomdlavuza we-hormone-refractory prostate,87,88 kunye nokunciphisa umngcipheko ngokupheleleyo. ye-11% kwiminyaka emi-2 xa kuthelekiswa ne-placebo.

Njengabesetyhini abafumana i-aclation hormonal ablation, amadoda anomhlaza womhlaza wesifo se-prostate ofumana unyango lwe-androgen-unyango unokuzuza kwi-bisphosphonate. Nangona unyango lwe-IV lwamathambo luvimbela ukulahleka kwethambo kwi-hip kunye nomgudu emadodeni onomdlavuza ongaphantsi kwe-prostate owafumana i-gonadotropin-ukukhulula i-hormone yonyango ye-agonist, i-89 enye i-dose ye-IV ye-zoledronic acid esandula kuboniswa ukuba ibangele ukwanda kwintlambo kunye nomlenze I-BMD (kunokuba kunqatshelwe ukugqithwa kwezigulane ezithe zafumana indawo ye-placebo). Ezi ziphumo zibonisa ukuba unyango lwe-b bisphosphonate yonyaka lungaba luncedo oluluncedo lokugcina ingqibelelo yamathambo kwi-androgen-inyanzelisayo yamadoda90 kwaye afana neziphumo ezifunyenwe kunye neshedyuli ephindwe rhoqo .91 I-risedronate yomlomo ngexesha lemihla ngemihla ye-2.5 mg sele iboniswe ukukhusela i-BMD ekulahlekeni kwintambo kwaye idibene ne-4.9% kwanda kwi-lumbar spine .92

Multiel Myeloma

Kwii-myeloma ezininzi, ukwanda kwe-clonal yeeseli ze-plasma ezinobungozi ngaphakathi kumnkantsi wethambo kubangela i-osteolysis kunye nokutshatyalaliswa kwamathambo, kubalwa ubuninzi bokugula okuhambelana nesifo. Izifundo ezininzi zibonise ukuba zombini i-pamidronate kunye ne-zoledronic acid inendima ebalulekileyo yokunciphisa i-hypercalcemia kunye ne-skeletal bone iziganeko ezinxulumene ne-myeloma, i-93-95 ibeka i-IV bisphosphonates kwiziko lonyango lwangoku ukukhusela nokuphatha i-myeloma ehambelanayo. isifo samathambo. Okwangoku, akukho datha yenkxaso yonyango lwe-bisphosphonate yezigulane ezine-myeloma eqhumayo, i-myeloma ngaphandle kwesifo sethambo esihambelanayo, okanye i-monoclonal gammopathy yokubaluleka okungachazwanga, kwaye akukho unyango lwe-bisphosphonate yomlomo olucetyiswayo ekulawuleni isifo se-skeletal esinxulumene ne-myeloma.

Ngenxa yokuba izigulana ezine-myeloma ezininzi zinesiganeko esiphezulu se-ONJ kuzo zonke izigulane ze-oncology ezifumana unyango lwe-bisphosphonate, ukhetho lwe-bisphosphonate, umyinge, kunye nobude bexesha luye lugxininiso lwempikiswano eninzi, ukukhula kwizikhokelo zenkcubeko ezivela kwi-American Society of Clinical I-Oncology96 kwaye, ngoku kutshanje, isigqibo esivela kwi-Mayo Clinic i-Myeloma Group97 ngesiseko sokuhlaziywa olubanzi lweencwadi ezikhulayo. Kwimvumelwano yokubambisana kweMayo, ukunyuswa kwenyanga rhoqo (ngenxa yengozi ephezulu ye-ONJ kwizigulane ezitholayo i-zoledronic acid) yayinomdla, ngokuyeka emva kwe-2 iminyaka xa izigulane zifumana ukuxolelwa kwaye azifuneki unyango lwe-myeloma. Ukuba unyango olusebenzayo luyafuneka, i-pamidronate ingaqhutyelwa kwishedyuli encitshisiwe yeenyanga ze-3. Nangona iQela lokuSebenza laseMyeloma yamazwe ngamazwe livumile ngokuvumelana nesigqibo seMayo, iqela licebise ukuba unyango lwe-pamidronate lungagcinwa emva kokuba isiguli sise-1 kunyaka wokukhutshwa kwekliniki kwaye ukuba ishedyuli yokunciphisa i-dosing ayibonwanga.98 Ngona kunjalo, nangona i-bisphosphonates ihlala Imbalulekileyo ebalulekileyo kwindlela yokwelapha kwi-myeloma isifo sesifuba, imibuzo malunga nokusetyenziswa kwabo okusemgangathweni.

Ezinye izigwenxa

Ukusetyenziswa kwe-bisphosphonates kwezinye izifo ezinobungozi ngaphantsi kwe-metastatic kwithambo, njenge-renal cell carcinoma, kuye kwaboniswa ukulibazisa ukuqala kunye nokuqhubela phambili kwesifo samathambo, i-99 ebonisa ukuba izigulane ezineemeko zeklinikhi ezingakholelwa ukuba zichaphazela i-skeleton nazo zingazuza kwi-bisphosphonate. unyango. Okwangoku, nangona kunjalo, idatha encinci yenkxaso yesiqhelo yokusetyenziswa kwe-bisphosphonate therapy kwezinye izinto ezimbi.

I-Bisphosphonate Therapy yabantwana

Nangona i-bisphosphonates isetyenziswe kakhulu kubantu abadala, kule minyaka ilishumi idlulileyo iye yaba yeyona nto iphambili kunyango lwe-OI, isifo samathambo esinofuzo esibonakaliswa kukuncipha kakhulu kwamathambo kunye nobuthathaka obunzima, obudla ngokubangelwa kukuguqulwa kofuzo lohlobo I-collagen. Irejimeni eyenziwe nguGlorieux100 ye-cyclic IV pamidronate (enikwe kwimijikelezo yeentsuku ze-3 rhoqo kwiinyanga ezi-2 ukuya kwiinyanga ze-4 kwi-dose yonyaka ye-9 mg / kg) isetyenziswe ngempumelelo kakhulu, ekhokelela kwi-88% yokwanda kwe-cortical thickness, i-46% ukwanda komthamo wamathambo e-trabecular, i-101 kunye nokuphuculwa okukhulu kwimeko yokusebenza. Kutshanje, uphando oluninzi luye lwabonisa ukuba i-alendronate yomlomo inokukhokelela ekunyukeni okukhulu kwe-BMD kwaye inokunciphisa iifractures kwi-OI echaphazela abantwana. ukusuka kwizigulane ezine-OI zibonisa izinga lokunyuka kwamathambo okubangelwa ukunyuka kwe-osteoclast ngokumalunga nomsebenzi we-osteoblast, okukhokelela ekulahlekeni kwethambo kunye nomjikelezo ngamnye wokulungisa. ukukhuthaza ukubunjwa kwamathambo, nangona kwimeko ye-collagen matrix engaqhelekanga. Enyanisweni, uhlalutyo lwe-histomorphometric ye-iliac crest biopsy specimens ezivela kwizigulane ezine-OI ezifumene unyango lwe-pamidronate zibonise ukwanda kwe-cortical thickness kunye nenani le-trabeculae kodwa akukho ukwanda kwe-trabecular thickness.102

Nangona unyango lwe-bisphosphonate lusekwe kakuhle kwi-OI kubantwana, idatha ingaphelelanga kwi-efficiency kunye nomngcipheko wengozi xa i-bisphosphonates isetyenziselwa abantwana abane-ostoporosis esecaleni kwisifo esingapheliyo (njenge-cystic fibrosis, i-rhumatoid rheumatoid arthritis, okanye i-anorexia nervosa) okanye abaye bavutha kakhulu. Ukuphononongwa ngokutsha kwenkqubo yokwenza i-bisphosphonate unyango kwabantwana nakwishumi elivisayo kunye ne-osteoporosis yesibini yagqitywa ukuba ubungqina obuncinane bukhona ukuxhasa ama-bisphosphonates njengonyango oluqhelekileyo, nangona unyango lwexesha le-3 iminyaka okanye ngaphantsi lubonakala lunyamezelekile. ukuphuhlisa izikhokelo ezicacileyo zokuxilonga nokuphatha zonke iintlobo ze-osteoporosis kubantwana.107

Ekugqibeleni, kunikezwe i-half-skeletal half-life-life of bisphosphonates kunye nobungqina bokuba i-pamidronate ifunyenwe kwiimpawu ze-urine ukuya kwi-8 iminyaka emva kokulawulwa, ukunakekelwa kwe-109 kuqinisekiswe xa kuthethwa ngonyango lwe-bisphosphonate kumntu oselula okanye kumantombazana amancinci afikelele ekuvuthweni kokuzalana kwishumi elishumi. unyango. Okwangoku, idatha kuphela, idatha ye-anecdotal iye yavavanya ukhuseleko lwexesha elide le-pamidronate110 okanye olunye unyango lwe-bisphosphonate ngexesha lophuhliso lomntwana.

I-Bisphosphonates ekwenzeni iiklinikhi isetyenziselwa ukunyanga i-osteoporosis, isifo sePaget sesithambo, i-metastasis yamathambo, i-myeloma eninzi, kunye neminye imiba yempilo kunye namathambo athathaka. Nangona i-bisphosphonates inconywa njengenye yezokwelapha zokuqala kwe-post-menopausal osteoporosis, uphando olwenziwe ngaphambili luye lwaxubusha imiphumo emibi yale nkalo yeyeza / amachiza. Kubalulekile ukuba izigulane zikhulume neengcali zabo zonyango malunga neendlela zokonyango zokulimala kunye / okanye iimeko.

UDkt Alex Jimenez DC, i-CCST Insight

Iinkxalabo zezonyango ezinxulumene neTransphons Treaty

I-Osteonecrosis yeJaw

Phakathi kweziganeko zeklinikhi ezinobungozi ezinxulumene nokusetyenziswa kwe-bisphosphonates, akukho namnye oye wafumana ingqwalasela enkulu kune-ONJ. Njengoko kuhlaziywe nguWoo et al, i-111 phantse zonke iimeko ze-ONJ (94%) zichazwe kwizigulane ezifumana iidosi eziphezulu ze-IV bisphosphonates (ikakhulukazi i-zoledronic acid kunye ne-pamidronate) kwiimeko ze-oncologic. Ukuxhaphaka kwizigulane ezine-myeloma zivela kwi-7% ukuya kwi-10%, ngelixa ukuya kwi-4% yezigulane ezinomdlavuza webele ziphuhliswe i-ONJ.111,112 Ngoku kutshanje, nangona kunjalo, ishedyuli yokunciphisa i-dosing kwizigulane ezine-myeloma, apho i-IV bisphosphonate inikwe inyanga nenyanga kwi-1. unyaka kwaye emva kweenyanga zonke ze-3 emva koko, kuboniswe ukunciphisa iziganeko ze-ONJ xa kuthelekiswa ne-infusions ye-bisphosphonate yenyanga.113

Nangona iziganeko ze-ONJ ziqikelelwa ukuba yi-1 kwi-10 ngezigulane ze-oncology ze-100, umngcipheko we-ONJ ubonakala uncinci phakathi kwezigulane ezitholwa ngonyango lomlomo we-bisphosphonate ye-osteoporosis, kunye neziganeko eziqikelelweyo malunga ne-1 kwi-10,000 ukuya kwi-1 kwi-100,000 unyango , nangona le ngqikelelo isekelwe kwidata engaphelelanga. I-114 iimeko ezinobungozi ezibonakalayo zibuhlwempuzekileyo emzimbeni, imbali yeendlela zamathambo okanye ukusetyenziswa kwamathambo, kunye nokubonakaliswa kwexesha elide kumayeza ephezulu e-bisphosphonate.115,116 Ingaba ukusebenzisa i-chemotherapy okanye i-glucocorticoid isebenzisa Umngcipheko ophezulu we-ON ungaziwa.117 Emva kokumiselwa, ukunakekelwa kwe-ONJ kuxhaswa ngokubanzi, kunye ne-rinses yomlomo, i-antibiotics, kunye ne-antibiotic engancinci, njengoko kubalulekile ukuphulukisa kwiimeko ezininzi.118 Nangona izikhokelo ezisekelwe kumqondiso ngeli xesha azizange esetyenziselwe naluphi na uhlobo oluthile lwesilwanyana okanye i-bisphosphonate, ingqalelo ngononophelo lwamazinyo okubandakanya i-cav yomlomo ukuhlolwa kwimiba yamazinyo esebenzayo okanye ekulindelekileyo, zombini phambi kokuqaliswa kwe-bisphosphonate kunye nonyango lonke, luya kuba luphambili.

Nangona ukusetyenziswa kwe-bisphosphonates kunye nophuhliso lwe-ONJ zidibaniswe nexeshana, ubuhlobo bokwahlukana aluzange luchongwe. Ngaloo ndlela, nangona iincwadi ezenzakalisayo zenzululwazi eziye zaphuhliswa ukususela ekubeni ubudlelwane phakathi kwonyango ye-bisphosphonate kunye ne-ONJ kwaqala ukuxelwa kwi-2003,119 imibuzo emininzi engundoqo ayiphenduli. Njengeyokuqala inxaxheba kule nkqubo, iqela elibanjwe nguMbutho we-American Society for Bone and Mineral Research lisandula ukunika inkcazo ecacileyo ye-ON njengobungqina be-bone ebonakalayo kwindawo engama-maxillofacial engaphilanga kwiiveki ze-8 emva kokuchongwa yimpilo I-114 Ngenxa yokungabi namandla okwangoku kwimeko yeziganeko eziyinyani, izinto ezinobungozi, kunye neendlela zonyango kwizinto zokuthintela kunye nokunyango, izifundo eziphambili nezisilwanyana kunye nokuhlolwa kwezilwanyana ezicwangcisiweyo, kuyafuneka ukuba zombini zichonge izigulane umngcipheko wophuhliso lwe-ONJ nokuqonda ngokubanzi umbutho phakathi kwe-bhonosphonate therapy kunye ne-ONJ.

Fibrillation yeArivri

Ukongeza kwenkxalabo ye-ONJ, enye inkxalabo yonyango ye-bisphosphonate, esandul 'ukukhanya, i-fibrillation ye-agrifu. Uvavanyo lwe-HORIZON oluQhathekayo lweFracture, apho izigulane ziphathwa rhoqo ngonyaka kunye ne-IV zoledronic acid, ukwanda kwenani lokubakho kwi-fibrillation echaphazelekayo (kuchazwa njengeziganeko ezibangelwa ukulaliswa kwezifo okanye ukukhubazeka okanye ukugwetywa ngokusongela ubomi) .14 I-etiology ye-electrophysiologic engaqhelekanga ayiyazi. Kungakhathaliseki ukuba amanye amalungiselelo e-bisphosphonate adibaniswa neerhafu ezikhulayo ze-fibrillation ye-atrial engaziwayo ngoku, kodwa ukuhlalutya kwe-post hoc yolwazi kwi-Triqual Fracture Intervention Trials120 kunye nokusukela kwi-large-based-control control control121 kukhombisa ukulungiswa phakathi kokulawulwa kwe-alendronate kunye nokwanda iziganeko ze-fibrillation ye-agriyo, nangona uphando oluthe lwabantu abakhulu olusisigxina-mthetho alubonanga ubungqina bengozi yokunyuka kwe-friday frillation okanye i-flutter ene-alendronate usetyenziso.122 Okwangoku, ukukhathazeka nge-fibrillation ye-atrial akubonakali kwandisa kwizigulane ezifumana i-risedronate, i-123 akukho izinga lokunyuka kwamafayili e-atrial elibonwa kwi-HORIZON I-Fracture Trial Trial, apho izigulane zamukelwa i-IV zoledronic acid emva kokuphazamiseka kwe-hip.38 Ngokucacileyo, uphando olongezelelweyo olunxulumene nolwalamano olunokwenzeka phakathi kokusetyenziswa kwe-bisphosphonate kunye ne-fibrillation ye-atrial kuqinisekisiwe phakathi kwabagqirha kunye nezigulane ei okwangoku ilawulwa okanye iqwalasela ukuqaliswa kwonyango lwe-bisphosphonate.

Ukuguqulwa kweThambo yokuThengisa

Ngenxa yokuba i-bisphosphonates inqanda umsebenzi we-osteoclast, kukho inkxalabo yokuba unyango olude lwe-bisphosphonate lukhokelela kwithambo elinqabileyo, elibonakaliswe ngokunyanzeliswa kokulungiswa kwamathambo, ukungakwazi ukulungisa i-microfractures yamathambo, kunye nokwanda kwe-fragility yamathambo. Nangona izinga lokunyuka kwe-microfractures lifunyenwe kwizinja eziphathwa ngamayeza aphezulu e-bisphosphonates, i-124 esi siphumo asibonakali siqhelekile phakathi kwabasetyhini be-postmenopausal abane-osteoporosis ephathwa ngomlomo okanye nge-IV ye-bisphosphonate therapy, i-22,125 nangona iimeko ezizimeleyo zokuguqulwa kwamathambo kunye nokunyanzeliswa. Iifractures ezinxulumene nazo ziye zabikwa.126,127 Nangona kunjalo, ixesha elifanelekileyo lonyango lwe-bisphosphonate ye-postmenopausal osteoporosis, kwaye phantse zonke ezinye iimeko ezisetyenziselwa i-bisphosphonates, zihlala zingacacanga.

Hypocalcemia

I-Hypocalcemia emva kokulawulwa kwe-bisphosphonate ininzi ilandela ukunyuka kwe-IV kwaye ingafumaneka kwizigulane ezinamazinga aphakamileyo okhushulwa ngamathambo e-osteoclast (njengezigulane ezinezifo zePaget ze-bone128 okanye umthwalo we-squitric tumor129), ngaphambili engaziwa i-hypoparathyroidism, umsebenzi we-130 ongasebenzi , okanye i-hypovitaminosis D ngaphambi kokuba unyango.131 Ukwelashwa kuxhaswa kakhulu, kunye ne-calcium kunye ne-vitamin D njengendlela efanele.

Impendulo evuthayo

Phantse i-10% ukuya kwi-30% yezigulana ezifumana i-nitrogen yokuqala ene-bisphosphonate infusion iya kufumana impendulo ebukhali yesigaba, edla ngokubonakaliswa yi-pyrexia yexeshana enxulumene ne-myalgias, arthralgias, iintloko, kunye neempawu ezinje ngomkhuhlane. Eli nqanaba lehla ngaphezulu kwesiqingatha ngokufakwa komntu okulandelayo, kangangokuba inqanaba le-2.8% lafunyanwa emva kokufakwa okwesithathu kuvavanyo lwe-HORIZON.14 Impendulo yesigaba esibi ikholelwa ekubeni sisiphumo semveliso ye-cytokine enegazi lomda? Iiseli ze-T.132 Ukunyanga kwangaphambili kunye ne-histamine receptor antagonists okanye i-antipyretics kunokunciphisa izehlo kunye nobukrakra beempawu phakathi kwabaguli abanokuchaphazeleka. Ngamaxesha athile ii-corticosteroids ziluncedo.

Impembelelo engathandekiyo yonyango lwe-bisphosphonate apho oogqirha kufuneka baqaphele ukuvutha komzimba (conjunctivitis, uveitis, episcleritis, kunye ne-scleritis). Le nkcenkcesho ifunyenwe ukuba yenzeke kunye neyomlomo kunye ne-IV bhosphosphonate. Kwisifundo esona sikhulu kunamhlanje, isiganeko se-0.1% sitholakale kwizigulane eziphathwe ngomlomo we-risedronate.133 Ngethamsanqa, iimpawu ze-ocular zihlala zixazulula kwiiveki ezimbalwa emva kokunqanyulwa kwe-bisphosphonate.

Ubuhlungu obukhulu beMusculoskeletal Pain

Nangona wonke uluhlu lwamalungiselelo omlomo kunye ne-IV bhonphosphonate uluhlu lweengxube ze-musculoskelet njengendlela echaphazelayo ingozi ekuchazeni ulwazi, i-US FDA imva nje ikhuphe isilumkiso esichaza ukuba kunokwenzeka ukuba intlungu enokuthi ingakwazi ukukhupha i-musculoskeletal intlungu eyenzekayo nayiphi na imeko emva kokuqaliswa kwonyango ye-bisphosphonate. Intlungu ebuhlungu ye-musculoskeal yahluke kwi-response phase acute ichazwe ngaphambili. Ambalwa amacala e-134 abiwe nge120 ekupheleni kwe-alendronate nakwi-2002 ye-risedronate ngokupheleleyo.2003 Ngelo xesha, izinto eziyimingcipheko kunye neziganeko zalo mphumo zibi ziyaziwa.

Ezinye iziganeko ezinokuthi zenziwe ngonyango lweBisphosphonate

Ezinye iingxaki ezinxulumene nokusetyenziswa kwemithi ye-oral kunye ne-IV eyaziwayo. Ukucatshiswa kwe-Esophageal kunye nokukhula kwamanzi kungenziwa nge-oral bhosphosphonate unyango, ngokukodwa kwizigulane ezinezifo zesifo segastroesophageal reflux okanye i-esophageal stricture. Ukugcinwa okunamandla kwithuba eliqhelekileyo le-30 ukuya kwi-60 imizuzu emva kokungena kunye neglasi yamanzi epheleleyo, kuxhomekeke kumlomo we-bisphosphonate ngomlomo, kunye nokusetyenziswa kweeveki kunokuba zilungiselelwe imihla ngemihla zingabinciphisa umngcipheko wemiphumo emibi. Kwizigulane ezingakwazi ukunyamezela umlomo we-bisphosphonates, izilungiso ze-IV (njengoko ziphawulwe ngaphambili) ngoku zivunywe yi-FDA kwaye azihambelani nefuthe le-gastroesophageal.

Amanani e-bisphosphonate kunye namazinga okunyusa ama-infusion kufuneka ahlengahlengiswe kwizigulane ezinomlinganiselo wokungazinzi. Ukuba zisetyenziswe kwizigulane ezinokubaluleka kwexabiso lokudala ngaphantsi kwe-30 mL / min, i-bisphosphonates kufuneka isetyenziswe. Ngokukodwa kwizigulane ezitholayo izilungiso ze-IV, i-bisphosphonates ingakhokelela ekudakaleni ngokukhawuleza komsebenzi wempuphu, i-136,137 mhlawumbi ngenxa yokuqokelela kwabo kwiindawo. Kwizigulane ezingenakukwazi ukufumana intsholongwane enokufumana unyango lwe-bisphosphonate ye-IV, umsebenzi wempuphu ngaphambili kwaye emva kokulawulwa kweziyobisi kufuneka kuqinisekiswe. Kwizigulane ezinobunzima bokunqongophala komzimba, i-oralphophophonates yomlomo ayikho nto ibangela ukuba kuqhutywe umonakalo kwimisebenzi yempondo, mhlawumbi ngenxa yokunyanzelwa kwabo embi kwinqanaba lezondlo kunye nokunciphisa i-short-term bioavailability.

Imibuzo engaphendulwanga

I-Bisphosphonates ibe kwaye iqhube isetyenziselwa ezinye iimeko ngaphandle kwembonakalo evunyiweyo ye-FDA yeyeza. Njengoko kuphawuliwe, ezi zibandakanya abantu abahlukahlukeneyo bezilwanyana ezinomzimba osiswini esiphambanisayo, amaqhekeza esiganeko, kunye nokungahlali ixesha elide. Abaninzi abasetyhini abasempilweni abanomdla nge-radiographic osteopenia okanye i-osteoporosis ngaphandle kwee-fractures kunye nabafazi be-postmenopausal abane-osteopenia kodwa ngaphandle kokuphazamiseka ngoku bafumana unyango lwe-bisphosphonate. Kuze kubekho uphando olongezelelweyo olujongene nale mibuzo ebalulekileyo yekliniki, kubalulekile ukuxelela izi gulane ukuba njengamanje asikho idatha efanelekileyo evela kwiilingo ezilawulwa kakuhle ukujonga ukuba zincedo okanye iingozi ezicatshangwa nale ndlela yokungenelela kwemithi.

Indima yeCalcium kunye neVithamini D

Nangona iinjongo ezintle zengcali ezininzi zinciphisa izidumbu kwizigulane zabo ngokusungula unyango lwe-bisphosphonate, ukubaluleka kokuqinisekisa i-vitamin D eyaneleyo kunye nokudla kwe-calcium ngaphambi nangemva kokuqala unyango lwe-bisphosphate. I-Hypovitaminosis D iyaqhelekileyo phakathi kwabantu abaninzi abanezigulane ezichazwe unyango lwe-bisphosphonate kwaye ngokuqhelekileyo eziqhelekileyo kwizigulane ezisebekhulile ezisoloko zithintela ukukhanya kwelanga, ukunciphisa ukutya okudliwayo okanye ukuphazamiseka kwemithi. Ukuntula u-vitamin D okanye ukusilela kunciphisa ukutywala kwe-calcium, okukhokelela kwi-hyperparathyroidism yesibini kunye nokulahleka kwe-skeletal calcium ukugcina i-normocalcemia. Ngako oko, phakathi kwabasetyhini abasebekhulile abane-osteoporosis, ukuphikelela kwe-hyperparathyroidism yesibini kwandisa ukunyuka kwe-BMD kwi-lumbar spine ekuphenduleni i-alendronate yeveki nganye.138 Nangona i-data ekhoyo njengamanje ayinikelanga ngokuvumelana malunga namazinga e-serum aphezulu ye-25-hydroxyvitamin D, i-30 ng / mL (i-75 nmol / L) okanye ngaphezulu kubonwa njengokwaneleyo; i-vitamin D ukuxiliswa kwenzeka kuphela xa amazinga aphezulu kune 150 ng / mL (374 nmol / L) .139 Ukuphononongwa ngokupheleleyo kweendima yevithamini D ekugcinweni kwempilo yesifo kunye neengcebiso zokutshintshwa kwe-vitamin D, nceda ufunde ukuhlaziywa kwangoku kwangoko kuHolick.139

Nangona izikhokelo zokugcina amanqanaba aphezulu e-vitamin D ziye zatshintsha kakhulu njengoko siqonda ukuba ukungonelanga kwe-vitamin D kunye nokunqongophala kuchaphazela inani elikhulu labemi kunokuba laliqatshelwe ngaphambili, iingcebiso zokufumana i-calcium eyoneleyo ziye zatshintshwa kancinane kuphela emva kokuba ziqwalaselwe yingcali. Iphaneli ehlanganiswe yiNational Institutes of Health kwi-1994.140 Iphaneli yagqiba ukuba i-calcium intake efanelekileyo iqikelelwa ukuba yi-1000 mg / d kubo bobabini abafazi be-premenopausal kunye ne-postmenopausal abafumana unyango lokutshintshwa kwe-estrogen kunye ne-1500 mg / d kubafazi be-postmenopausal abangayifumani i-estrogen. Amadoda angaphantsi kweminyaka eyi-65 aqikelelwa ukuba afune i-1000 mg / d ye-calcium kunye namadoda amadala kuneminyaka eyi-65 ukuba afune i-1500 mg / d.140 Iziphakamiso zamva nje ezivela kwi-National Osteoporosis Foundation zicebise ukuba i-calcium ithathe i-1000 mg / d kumadoda omabini. kunye nabasetyhini abangaphantsi kweminyaka eyi-50, kunye nokunyuka ukuya kwi-1200 mg / d ukusuka kwiminyaka eyi-50 ukuya phambili.141 Ezi ngcebiso zihambelana neBhodi yokutya kunye neZondlo ze-Institute of Medicine.142 Ezinye iingcebiso malunga nokutya kwe-calcium kubantwana zicacisiwe. kuzo zombini izikhokelo zeNational Institutes of Health and Institute of Medicine.140,142

isiphelo

Ukususela ekuqalisweni kwabo kwiklinikhi, i-bisphosphonates iguqule ukhathalelo lweklinikhi yoluhlu lweengxaki ze-skeletal ezibonakaliswe ngokugqithisileyo kwe-osteoclast-mediated bone resorption. Ngokufanelekileyo, ukusetyenziswa okunolwazi kunye nokuqonda kwe-bisphosphonates kunika inzuzo ecacileyo yekliniki kwizigulane ezikhethwe ngokucophelela ezigqithisa iingozi ezinxulumene nokusetyenziswa kwe-bisphosphonate. Ukugcinwa kwekhalsiyam eyaneleyo kunye nevithamin D kubalulekile kuzo zonke izigulana ezifumana unyango lwe-bisphosphonate.

Imibulelo

Siyabulela uJames M. Peterson ngoncedo ngamanani.

Ukulungiselelwa kweli nqaku kwakunikwe inkxaso kwi-Award Career Award kuDkt Drake.

UGqr Khosla ufumene inkxaso yophando evela kwiProcter kunye neGamble kwaye usebenze kwibhodi yeengcebiso yeNovartis.

uluhlu lwamagama

• I-ATP - adenosine triphosphate
• I-BMD - ithambo lesityeli samaminerali
• I-DXA - i-x-ray absorptiometry
• I-FDA - Ulawulo lwezoKutya noLawulo lweeMithi
• I-GIO - i-osteoporosis eyenziwe nge-glucocorticoid
• I-HORIZONI - IziPhumo zeMpilo kunye neNgcembelelo eNciphise nge-Zoledronic Acid Kanye ngonyaka
• IV - intravenous
• OI - osteogenesis imperfecta
• I-ONJ - osteonecrosis yomhlathi
• PPi - i-pyrophosphate engahambelaniyo
• I-hormone ye-PTH-parathyroid
• I-WHI – iNyathelo lezeMpilo yabaseTyhini

Imihlathi

Ukutshintshwa komntu ngamnye kweli nqaku akufumaneki.

Ngokutsho kwenqaku elingasentla, nangona ukusetyenziswa kwee-bisphosphonates kumsebenzi wezonyango kunika abaqeqeshi bezempilo ngeendlela ezintsha zonyango zokuphazamiseka kwamathambo, �uphando olongezelelekileyo lusafuneka. Ulwazi olubhekiselele kwiZiko leSizwe loLwazi lweBiotechnology (NCBI).�Ubungakanani bolwazi lwethu buphelele kwi-chiropractic kunye nokulimala komgogodla kunye neemeko. Ukuxoxa ngalo mbandela, nceda uzive ukhululekile ukubuza uGqr. Jimenez okanye uqhagamshelane nathi apha915-850-0900 .

Ikhutshwe nguDkt. Alex Jimenez

 

Imixholo eyongezelelweyo: I-Pain Back Pain

Umqolo obuhlunguSesinye sezona zizathu zixhaphakileyo zokukhubazeka kunye neentsuku eziphosiweyo emsebenzini kwihlabathi liphela. Intlungu ebuyela emva sisizathu sesibini esiqhelekileyo sokundwendwela i-ofisi kagqirha, ngaphezulu kunosulelo oluphezulu lokuphefumla. Ngokumalunga neepesenti ezingama-80 zabemi baya kuba neentlungu zentlungu emva kanye ebomini babo. Umqolo sisakhiwo esintsonkothileyo esenziwe ngamathambo, amalungu, iigaments, kunye nezihlunu, phakathi kwezinye izicwili ezithambileyo. Ngenxa yoku, ukwenzakala kunye / okanye iimeko ezixhalabisayo, ezinje ngedisni, ekugqibeleni unokukhokelela kwiimpawu zentlungu. Ukulimala kwezemidlalo okanye ukulimala kwengozi yeemoto ngokuqhelekileyo kubangelwa yintlungu yokubuhlungu, kodwa ngamanye amaxesha ukuhamba kwezinto ezilula kunokuba neziphumo ezibuhlungu. Ngethamsanqa, ezinye iindlela zokhathalela unyango, ezifana nokunyamekelwa kwe-chiropractic, kunokunceda ukubuyisela intlungu emva kokusetyenziswa kwemilenze kunye nokunyanzeliswa kwemigaqo, ekugqibeleni ukuphucula intlungu.

 

INGXELO EBALULEKILEYO: Ukwelashwa kwe-Chiropractic Hip Pain Treatment